Researchers have discovered a new mechanism that plays a key role in the development of alcohol-related liver disease



Alcohol-related liver disease is among the most common causes of morbidity and mortality worldwide. Because of the incomplete understanding of the factors contributing to disease progression, liver transplantation remains the only treatment available. A team led by Tim Hendricks of the Department of Laboratory Medicine at Medoni Vienna has discovered a new mechanism that plays an important role in the development of the disease. With an improved understanding of the molecular background, researchers are now laying the foundations for developing new treatment modalities. The results of the study were published in the prestigious scientific journal “Goat”.

As part of their investigation, conducted in collaboration with a team from the University of California San Diego, MedUni Vienna researchers have identified the previously unknown function of the polymeric immunoglobulin receptor (pIgR) in alcohol-related liver disease. Preclinical studies have shown that secretion of certain PIgR-mediated antibodies (immunoglobulin A or IgA) into the intestine plays an essential role in protecting the liver against alcohol-induced damage.

The development of alcohol-related liver disease is characterized by increased intestinal permeability or “leaky gut,” which enables bacteria (and their by-products) to gain access to the liver, triggering an inflammatory reaction. Secretion of IgA in the gut is an important strategy for protection against invading pathogens. Immunoglobulin A levels in the gut are controlled by pIgR, which binds to and transports IgA before it is deposited in the inner layer of the intestine (intestinal lumen).

Promising basis for new therapies

“Our study revealed an accumulation of pIgR and IgA in the livers of patients with alcohol-related hepatitis, which is an indicator of defects in the transport and secretion of immunoglobulin A,” said lead author Tim Hendrikx from the Department of Laboratory Medicine at MedUni Vienna. With an explanation of one of the details in the results. Using several animal models, researchers have shown that low levels of IgA in the intestines of mice without PIgR exacerbate alcohol-induced liver complications (steatohepatitis). The blood of mice without PIgR also showed evidence of increased bacterial transmission. In addition, the research team discovered a molecular mechanism that partially restores IgA levels in the intestine, thereby alleviating alcohol-induced liver disease in mice without PIgR.

Alcohol-related liver diseases – ranging from mild steatosis (fat buildup) to cirrhosis – are among the most common chronic liver diseases worldwide, and are a leading cause of morbidity and mortality. Although much progress has been made, treatment of alcohol-related liver damage remains suboptimal, and liver transplantation remains the only treatment. Hence, a better understanding of the molecular mechanisms behind disease development is an unmet need.

Our data show that PIgR dysfunction in the liver exacerbates alcohol-related liver disease due to an impaired antimicrobial response by IgA in the gut. This means that enhancing PIgR in the liver or increasing IgA levels in the intestine could be a promising starting point for new treatment options for alcohol-related liver disease.Tim Hendrix commented, summarizing the significance of the findings.

Source:

Journal reference:

Hendrix, T.; et al. (2023) PIgR-mediated hepatic IgA secretion limits bacterial translocation and prevents ethanol-induced liver disease in mice. Gut. doi.org/10.1136/gutjnl-2022-328265.



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